Pain is experienced when the free nerve endings which constitute the pain receptors in the skin as well as in certain internal tissues are subjected to mechanical, thermal, chemical or other noxious stimuli. The pain receptors (nociceptors) can transmit signals along afferent neurons into the central nervous system and then to the brain. The causes of pain can include inflammation, injury, disease, muscle spasm and the onset of a neuropathic event or syndrome. Ineffectively treated pain can be devastating to the person experiencing it by limiting function, reducing mobility, complicating sleep, and dramatically interfering with the quality of life.
The trigeminal sensory nerves (afferents) innervate and transmit to the brain most of the sensory signals from the face and anterior head. Pain involving the trigeminal nerve and ganglion arises in many different medical situations and presents unique problems to pain therapists and doctors. Chronic pain due to syndromes such as trigeminal neuralgia, atypical facial pain, anesthesia dolorosa, post-herpetic neuralgia, cancer of the head and neck, migraine headaches, and temporomandibular joint pain are examples of very different pain syndromes that all involve the trigeminal system and which present clinical challenges that are peculiar to this nerve distribution. In addition to chronic pain states, there are clinical situations where facial and head pain is associated with acute trauma such as an abscessed tooth, a headache or a direct injury to the face and/or head such as a laceration or a burn. Further, medical procedures such as common dental work and facial plastic and/or cosmetic surgery may elicit considerable pain, as well as discomfort and anxiety.
Among syndromes associated with facial pain is trigeminal neuralgia, also called “tic duloreaux” which is among the most debilitating facial pain syndromes. Trigeminal neuralgia usually begins after the age of 40, is slightly more common in women and has an incidence of approximately 4-5 per 100,000 persons (Khorami and Totals (2001) eMedicine Journal, Vol. 2). The primary symptom of trigeminal neuralgia is the sudden onset of severe, sharp facial pain, usually without warning. The quick bursts of pain are described as “lightening bolt-like”, “machine gun-like” or “electric shock-like”. The pain is generally on one side of the face and is spasmodic, coming in short bursts lasting a few seconds which may repeat many times over the course of a day. Trigeminal neuralgia can involve one or more branches of the trigeminal nerve and the causes are varied. Pharmacologic treatments include anti-seizure medications such as carbamazepine (Tegretol, Carbatrol), phenyloin (Dilantin), clonazepam (Klonopin), gabapentin (Neurontin), and lamtrignine (Lamictal), tricyclic antidepressants such as amitriptyline (Elavil) and muscle relaxants such as baclofen. The treatments generally have limited efficacy and many patients eventually undergo an invasive procedure. The procedural interventions often involve the direct manipulation of the trigeminal ganglion and include microvascular decompression, alcohol injection aimed at destroying pain fibers, glycerol injection aimed at selectively destroying pain-transmitting fibers, percutaneous radiofrequency rhizotomy, pulse radio frequency and gamma-knife. The pain relief from these procedures can be successful in a percentage of these patients, but the relief can be short-lived and often facial pain returns. Significant procedural pain and long term morbidity may also be associated with such treatments.
Atypical Facial Pain (ATFP) is a syndrome encompassing a wide group of facial pain problems. ATFP can have many different causes but the symptoms are all similar. Facial pain, often described as burning, aching or cramping, occurs on one side of the face, often in the region of the trigeminal nerve and can extend into the upper neck or back of the scalp. Although rarely as severe as trigeminal neuralgia, facial pain is continuous for ATFP patients, with few, if any periods of remission. Some studies propose that ATFP is an early form of trigeminal neuralgia, but there is no agreement at this time. Drug treatments for ATFP are similar to what is prescribed for trigeminal neuralgia including anti-seizure medications and tricyclic antidepressants with limited effectiveness.
Anesthesia dolorosa is one of the most dreaded complications of neurosurgery and is considered to be non-reversible. The two main symptoms of anesthesia dolorosa are facial numbness (much like the numbness from a dental anesthetic injection) and constant pain. The pain is usually burning, pulling or stabbing but can also include a sharp, stinging, shooting or electrical component. Pressure and “heaviness” can also be part of the pain symptoms and often there is eye pain. Cold can increase the feeling of numbness sometimes making the face feel frozen. Anesthesia dolorosa occurs when the trigeminal nerve is damaged by surgery, physical trauma or as a complication of surgery to correct a condition such as trigeminal neuralgia. Topical treatments with capsaicin are used to help manage the pain and discomfort, while topical clonidine has been tested in a few cases but no single treatment has been found that resolves all of the pain of this condition.
Post-herpetic neuralgia is pain that remains after the rash from shingles (herpes zoster) has healed. Shingles is an infection of the nerves caused by the varicella-zoster virus, which is the same virus that causes chickenpox. About one-third of the people who get shingles will get post herpetic neuralgia. The pain of post herpetic neuralgia may be constant, stabbing, aching, or burning and can last for months to years after the shingles outbreak.
It is predicted that approximately 65,000 Americans will be diagnosed with head and neck cancers this year, this represents about 3% of all cancers diagnosed in the United States (American Cancer Society). Close to 60% of head and neck cancer patients report long-term pain with up to 25% claiming moderate or severe pain (List and Stracks (2000) Curr. Opin. Oncol., 12:215-20). The trigeminal nerves and ganglion are likely to mediate most of the head and facial pain in these patients and sometimes are directly affected by the cancerous growth. The recommended treatment for most cancer patients with mild to severe pain is opioid therapy such as hydrocodone, codeine, oxycodone, morphine, fentanyl and hydromorphone. Opioid therapy has a multitude of problems including systemic effects away from the site of pain stimulation. Furthermore, opioids are highly addictive and patients build up tolerance to the drugs quickly resulting in higher and higher doses being administered.
Migraine headaches affect more than 29.5 million people in the United States. The typical migraine headache is throbbing or pulsatile, it builds up over a period of 1-2 hours and lasts from several hours to a whole day. Pain intensity is moderate to severe and can be debilitating and often causes nausea and vomiting. Of particular interest to clinicians who study migraine headaches is the superior trigeminal division (the ophthalmic division). This division innervates the forehead, eyebrow, eyelid, anterior scalp, nose and contents of the orbit thus giving an explanation for the pain localization along with the visual aura that is common with migraine headaches. Common treatments for migraine headaches include beta-blockers such as propranolol (Inderal) and Atenolol, tricyclic antidepressants, triptans, ergotamines, anti-seizure drugs and calcium channel blockers. Many of these drugs have systemic side effects and limited effectiveness.
Acute facial pain can arise in patients undergoing common dental procedures such as tooth extraction, root canal surgery and surgery for dental implants and dental prostheses. Acute dental pain can also arise from dental/gingival disease, other conditions such as an abscessed tooth or a bacterial infection or injury, that arise separately from planned dental procedures. Most dentists use topical anesthetics such as benzocaine, eugenol and forms of xylocaine to numb various areas for minor procedures or before injection of a local anesthetic. For most procedures a dentist will inject a local anesthetic such as lidocaine, xylocaine and marcaine to create a nerve block at or around the site where dental work needs to be done. Local anesthetics numb the area where they are injected and eliminate the acute pain of most procedures. In addition to the pain of administration, another main disadvantage of local anesthetics, especially for routine dental procedures, is that numbness and loss of sensation in the facial region will usually last for several hours after the dental procedure is finished.
Facial plastic surgery is becoming a very common procedure with several million procedures done in the United States each year. The procedures range from necessary repair of damage such as lacerations or broken bones to elective cosmetic surgeries such as face lifts, rhinoplasties, skin rejuvenation, etc. For many of these procedures local anesthetics are used (the patients are not under general anesthetic) and as with dental procedures, the local anesthetics can be painful to administer and include the problem of lingering numbness lasting for hours after the procedure is finished. In addition, depending on the surgery performed, patients experience varying levels of post-operative pain after the anesthetic wears off.
Pain treatment of almost any type usually includes some form of analgesic agent or drug. Analgesic drugs are usually classified into three groups: non-opioid drugs, opioid drugs, and co-analgesic drugs, also known as adjuvants. Non-opioid analgesic drugs include acetaminophen and non-steroidal anti-inflammatory drugs or NSAIDs. Opioid drugs, sometimes referred to as “narcotics”, include natural substances such as morphine, and semi-synthetic and synthetic substances. Co-analgesic medications are drugs that have a primary use other than pain relief, but also help produce analgesia for some painful conditions.
Opioid drugs are commonly used to relieve pain. However, their usefulness is limited by the tolerance and dependence that normally develops on chronic treatment. Opioid drugs such as morphine can be addictive and can have central nervous system-mediated side effects such as respiratory and cardiac depressions and drowsiness. Additionally, opioid drugs suffer from frequent side effects such as nausea, vomiting and constipation.
Therapeutic drugs are delivered by a number of routes including, for example, oral administration, intravenous injection, intramuscular injection and subcutaneous injection. For patients suffering procedural, acute or chronic pain associated with the trigeminal nerve, one of the main problems with conventional drug delivery with analgesic agents is the lack of localized pain relief due to systemic distribution of the agent. Often larger dosages need to be administered to achieve an effective concentration of the drug at a desired site. With higher doses of an analgesic agent, there is the additional problem of limited efficacy relative to the increase in undesired side effects due to the systemic distribution of the agent. Treatments consisting of localized but invasive interventions directly to the trigeminal nerve have a significant disadvantage due to the lack of selectivity and/or reversibility of the intervention and the fact that these procedures can, by themselves, cause additional facial nerve problems including anesthesia doloroso, persistent numbness and nerve deafferentation. An additional problem with conventional treatments for trigeminal nerve-associated pain, especially with invasive procedures, is the high level of skill, training and equipment required by the medical team which can make treatment expensive and impractical for widespread use.
Intranasal administration has been used for systemic delivery of several therapeutic agents, for example, insulin, thryrotropin-releasing hormone, and vasopressin. Using an intranasal or other mucosal route for systemic delivery of a therapeutic agent allows for ease of administration and the ability to bypass intestinal degradation and first pass hepatic metabolism of the therapeutic agent. There are times when it is desirable to not have systemic distribution of a therapeutic agent or to have a therapeutic agent targeted to a localized or regional area. For example, intranasal drug delivery has been used to bypass the blood-brain barrier and deliver substances to the central nervous system (CNS) and the brain. It has been demonstrated that large molecules such as polypeptides, peptides, oligonucleotides or DNA plasmids can be delivered directly to the CNS via specific uptake routes within the nose such as the axonal and perineural vascular/lymphatic pathways of the olfactory and trigeminal nerves (Frey II (2002) Drug Delivery Technology, 2:46-49; Thorne et al. (2004) Neuroscience, 127:481-496). However, while there is evidence that various therapeutic agents can be delivered to the brain by an intranasal route and that the agents may travel along perineural pathways, there is no known method utilizing these pathways to specifically target the trigeminal nerve system for localized or regional analgesia in individuals suffering from trigeminal nerve-associated pain.
Despite a wide range of medical treatments, trigeminal nerve-associated pain, in many different forms and situations, continues to affect millions of people. Thus new methods for treating an individual for trigeminal nerve-associated pain are needed to directly target the trigeminal nerve system with analgesic agents and deliver analgesia to facial or head regions with minimal central nervous system effects or systemic side effects.